The ontogeny of haematopoietic niches in vertebrates is essentially unknown. Here we show that the stromal cells of the caudal haematopoietic tissue (CHT), the first niche where definitive ...haematopoietic stem/progenitor cells (HSPCs) home in zebrafish development, derive from the caudal somites through an epithelial-mesenchymal transition (EMT). The resulting stromal cell progenitors accompany the formation of the caudal vein sinusoids, the other main component of the CHT niche, and mature into reticular cells lining and interconnecting sinusoids. We characterize a zebrafish mutant defective in definitive haematopoiesis due to a deficiency in the nascent polypeptide-associated complex alpha subunit (NACA). We demonstrate that the defect resides not in HSPCs but in the CHT niche. NACA-deficient stromal cell progenitors initially develop normally together with the sinusoids, and HSPCs home to the resulting niche, but stromal cell maturation is compromised, leading to a niche that is unable to support HSPC maintenance, expansion and differentiation.
Congenital dyserythropoietic anemias (CDAs) are phenotypically and genotypically heterogeneous diseases. CDA type II (CDAII) is the most frequent CDA. It is characterized by ineffective ...erythropoiesis and by the presence of bi- and multinucleated erythroblasts in bone marrow, with nuclei of equal size and DNA content, suggesting a cytokinesis disturbance. Other features of the peripheral red blood cells are protein and lipid dysglycosylation and endoplasmic reticulum double-membrane remnants. Development of other hematopoietic lineages is normal. Individuals with CDAII show progressive splenomegaly, gallstones and iron overload potentially with liver cirrhosis or cardiac failure. Here we show that the gene encoding the secretory COPII component SEC23B is mutated in CDAII. Short hairpin RNA (shRNA)-mediated suppression of SEC23B expression recapitulates the cytokinesis defect. Knockdown of zebrafish sec23b also leads to aberrant erythrocyte development. Our results provide in vivo evidence for SEC23B selectivity in erythroid differentiation and show that SEC23A and SEC23B, although highly related paralogous secretory COPII components, are nonredundant in erythrocyte maturation.
We report that lack of crossover along one chromosome arm is associated with high-frequency occurrence of recombination close to the opposing arm's centromere during zebrafish meiotic recombination. ...Our data indicate that recombination behavior on the two arms of a chromosome is linked. These results inform mapping strategies for telomeric mutants.
IgA antibodies against tissue transglutaminase (TTGA) and endomysium (EMA) are sensitive and specific markers for celiac disease (CD). Data correlating TTGA and EMA levels with degree of villous ...atrophy are limited. We compared duodenal histopathology in pediatric CD patients with TTGA and EMA serologies, symptoms, height, and weight.
We identified 117 pediatric patients retrospectively who had serologic testing for IgA TTGA and IgA EMA and duodenal biopsies graded by modified Marsh criteria as 0-3c. Data were analyzed with Spearman rank correlation and multinomial logistic regression.
IgA TTGA (r = .704, P < .001) and IgA EMA (r = 0.740, P < .001) correlated with intestinal villous atrophy in pediatric CD patients by Spearman rank correlation. Similar correlations were found in a subset of 23 patients younger than 3 years of age. Multinomial logistic regression revealed increased probability of Marsh 3a or greater changes with increasing TTGA or EMA levels. Strongly positive antibody levels (TTGA >100 units or EMA titer >1:1280) were highly specific (>98%) for Marsh 3a or greater lesions. Among symptoms, abdominal distention and diarrhea were associated with abnormal histology.
IgA TTGA and EMA levels correlate with duodenal villous atrophy in pediatric CD patients. IgA TTGA >100 or EMA >1:1280 were nearly always associated with CD histopathology. With further validation of this observation, strongly positive titers might be considered sufficient for diagnosis of pediatric patients at risk for CD. Symptoms, height, and weight are not reliable predictors of CD.
A novel magnetically actuated 8/spl times/8-port MEMS-based fiber-optic switch is described. Fiber-to-fiber insertion loss measurements of six 8/spl times/8 switch units show average and worst-case ...insertion loss of 1.3 dB and 2 dB, respectively. Low insertion loss is achieved through a unique MEMS design that uses anisotropically etched single-crystal silicon sidewalls to provide a global mechanical alignment stop for an array of MEMS mirrors. This alignment surface produces a uniform and repeatable mirror angle across the mirror array. Mirror misalignment is attributed to the surface roughness of the silicon sidewalls. Repeated interferometric measurements of the mirrors of 24 8/spl times/8 switch units show repeatability of the mirror angle of 3/spl times/10/sup -3/ degrees, while the uniformity of the mirror angle across the MEMS array is 2/spl times/10/sup -2/ degrees, in agreement with the angular error predicted from measurements of sidewall surface roughness. In turn, the average repeatability and uniformity of the insertion loss are 0.01 dB and 1 dB, respectively, in agreement with predictions based on the interferometric measurements. Finally, the unique dynamics of the magnetic actuation and electrostatic addressing scheme are described. Measurements show that fast switching can be achieved by driving the mirrors with a magnetic pulse that is faster than the mechanical resonant frequency of the mirror, relying on an electrostatic clamping force to capture the mirror as it overshoots the magnetic field angle. This actuation scheme is shown to result in switching times of 8.5 ms to 13.5 ms, but requires accurate control of the kinetic energy of the mirror.
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